Kinins, derived via the kallikrein-kinins pathway, have been demonstrated to affect the growth and metastasis of tumors through effects on cell growth and invasiveness. Four kinins (natural agonists) are responsible for the majority of bioactivities of this family of mediators. They include: bradykinin (BK), kallidin (KD or Lys-BK), desArg9 bradykinin (DBK) and desArg9 kallidin (Lys-DBK). These kinins are known to activate two membrane-bound receptors which have been identified as the BKB1 (agonists: DBK and Lys-DBK) and the BKB2 (agonists: BK and Lys-BK) subtype (Leeb-Lundberg et al., Pharmacol. Rev. 57: 27-77, 2005).
BKArg Pro Pro Gly Phe Ser(SEQ ID NO:1)Pro Phe Arg Lys-BKLys Arg Pro Pro Gly Phe(SEQ ID NO:2)Ser Pro Phe Arg desArg9BKArg Pro Pro Gly Phe Ser(SEQ ID NO:3)Pro Phe Lys-desArg9BKLys Arg Pro Pro Gly Phe(SEQ ID NO:4)Ser Pro Phe
The BKB1 receptor (BKB1-R) subtype is not present under normal conditions, whereas the BKB2 receptor subtype (BKB2-R) is normally present on many cell types. Inducible BKB1-Rs are expressed in neurons, endothelial, smooth muscle and blood cells, and are involved in various types of inflammation, such as, but not limited to, asthma and arthritis, diabetes (type I and II-obesity) and various types of vasculopathies as well as central and peripheral neuropathies (pain) (Leeb-Lundberg et al., Pharmacol. Rev. 57: 27-77, 2005).
Peptidic BKB1-R antagonists have been described in the literature (Neugebauer et al., Can. J. Physiol. Pharmacol. 80: 287-292, 2002). Other peptidic BKB1-R antagonists have been disclosed in various published patent documents (WO97/09346, U.S. Pat. No. 6,075,120, U.S. Pat. No. 5,863,899, U.S. Pat. No. 5,849,863, U.S. Pat. No. 5,843,900, U.S. Pat. No. 5,834,431, U.S. Pat. No. 5,750,506, U.S. Pat. No. 5,700,779, U.S. Pat. No. 5,635,593, U.S. Pat. No. 5,610,140, U.S. Ser. No. 09/242,751, WO98/07746). The antagonists used in this invention have been previously disclosed in U.S. Ser. No. 10/405,088.
Some cancers express, release and/or use peptides acting via autocrine/paracrine regulatory pathways to stimulate growth, angiogenesis and to modulate apoptosis. These cancers can also express the receptors activated by these peptides at the surface of many cells. Many other agents such as, but not limited to, Endothelins, Gastrin-releasing peptides, Ghrelin, Luteinizing Hormone-Releasing Hormone, Somatostatin, Vascular Endothelial Growth factor, have been identified as peptidic morphogens (phenotype modulators), growth regulators, pro-mitogens or growth factors.
A number of publications (reviewed by Stewart, Curr. Pharm. Des. 9: 2036-2042, 2003; Calixto et al., Brit. J. Pharmacol. 143: 803-818, 2005 and Leeb-Lundberg et al., Pharmacol. Rev. 57: 27-77, 2005) and patents (WO9964039; U.S. Pat. No. 5,849,863; U.S. Pat. No. 5,935,932) have alluded to the use of bradykinin antagonists as anti-cancer agents. However, the mechanisms of action of these compounds have not been clearly, even less fully, defined, as these compounds may be:                (i) anti-neoplastic (blocking basal and/or stimulated cell growth and proliferation);        (ii) anti-angiogenic (blocking the sprouting of new capillary blood vessels);        (iii) anti-migratory (blocking the invasiveness of cancer cells leading to metastasis);        (iv) and/or else.        
Some of the proposed compounds may be unrelated to their ability to solely antagonize either BK receptors for these compounds are not specific BK receptor antagonists (Stewart et al., Immunopharmacology 36: 167-172, 1997).
Recent studies have reported that the BKB1-R subtype is expressed in a variety of tumors. Those include: prostate, renal, gastric and esophageal carcinomas. In addition, cancer cell lines such as PC-3, LNCaP and astrocytic tumor cells were also found to express the BKB1-R (Taub et al., Cancer Res. 63: 2037-2041, 2003; Calixto et al., Brit. J. Pharmacol. 143: 803-818, 2005; Leeb-Lundberg et al., Pharmacol. Rev. 57: 27-77, 2005).
Cell growth and proliferation of cancerous PC-3 cells in vitro was stimulated by a BKB1-R agonist (desArg9-BK) and this growth was blocked by [Leu8]desArg9-BK, a BKB1-R antagonist (Taub et al., Cancer Res. 63: 2037-2041, 2003). However, basal growth and proliferation of PC-3, LNCaP and S-180 cells were not affected by BKB1-R antagonists (Taub et al., Cancer Res. 63: 2037-2041, 2003; Calixto et al., Brit. J. Pharmacol. 143: 803-818, 2005;).
Angiogenesis is another important aspect of cancer prognosis where the sprouting (formation and growth) of new capillary blood vessels within the tumor is a necessary step for tumor growth and invasiveness. Kinins are involved in the mechanisms of wound healing and angiogenesis and the two BK receptor subtypes appear to be implicated to various degrees. However, some studies suggest that the induced BKB1-R subtype is involved in the promotion of angiogenesis, whereas others propose that it is the constitutive BKB2-R subtype that is playing the major role (Stewart, Curr. Pharm. Des. 9: 2036-2042, 2003).
Another important aspect about the treatment of various forms of cancer and related conditions, is that anti-cancer chemotherapeutic agents are associated with complications such as the development of neuropathy, known as chemotherapy-induced neuropathy, which limit the dose and duration of anti-cancer treatments.
Depending on the antineoplastic substance used, the neuropathy can be (i) a pure sensory and painful neuropathy (caused by treatment with platinum-based compounds such as cisplatin, oxaliplatin, carboplatin, vinorelbine, gemcitabine, capecitabine)) or (ii) a mixed motor and sensory neuropathy that can involve and englobe the autonomic nervous system (caused by treatment with either taxanes (paclitaxel (=Taxol), docetaxel) or other agents (vinblastine, vincristine, vindesine, estramustine, suramin). Little is known about the mechanisms responsible for the development of neuropathy. Up to now, no drug is available to reliably prevent or cure chemotherapy-induced neuropathy (Ocean and Vahdat, Support Care cancer 12: 619-625, 2004).
BKB1-R antagonists have been reported to alleviate painful diabetic neuropathy (PDN) in various animal models of both Type I and Type II-obesity diabetes, nerve injury and other conditions, where BKB1-R are induced upon general inflammation (Leeb-Lundberg et al., Pharmacol. Rev. 57: 27-77, 2005).
The inventors formulated that kinins may mediate neuropathy through a direct action at induced BKB1-Rs and increase pain. These evidences suggest that blockade or antagonism of the actions of kinins may be useful for the treatment of chemotherapy-induced neuropathy of various etiologies and combinations.